The mechanisms for the antimicrobial activities of bacitracin, polymyxin, and EM49 will be studied. These three antibiotics all operate at the membrane level and interact with specific membrane lipids. The molecular basis for bacitracin induced membrane permeability changes will be examined. In addition, the ternary complex formed between bacitracin, divalent cations and isoprenyl pyrophosphates will be studied using magnetic resonance techniques to define the types of chemical forces contributing to the stability of this specific lipid-peptide complex. A working model is proposed for the selective action of EM49 and polymyxin against gram negative bacteria. It is proposed that these two antibiotics displace divalent cations from the outer membrane with gram negative bacteria thereby releasing outer membrane components into the media. Structural damage to the outer membrane may make the organism osmotically fragile and the inner membrane lyse. A number of experimental approaches are proposed to test this model.